Identification of TMEM230 mutations in familial Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson’s disease or parkinsonian disorders. The pathogenesis of Parkinson’s disease remain largely elusive. Here, we report a novel genetic locus for an autosomal dominant, clinically typical and Lewy body confirmed Parkinson’s disease on the short arm of chromosome 20 (20pter-p12) and TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. The disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide the first genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson’s disease, with novel implications in understanding the pathogenic mechanism of Parkinson’s disease and for developing rational therapies.